Metabolic flexibility maintains proliferation and migration of FGFR signaling–deficient lymphatic endothelial cells
| Autor: | Hongyuan Song, Ping Li, Longhou Fang, Fei Han, Pengchun Yu, Jie Zhu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
FGFR
fibroblast growth factor receptor cell migration FGFR Inhibition PPAR peroxisome proliferator–activated receptor Peroxisome proliferator-activated receptor Fibroblast growth factor Biochemistry CPT1A Downregulation and upregulation AMP-activated protein kinase cell metabolism FAO fatty acid β-oxidation 2DG 2-deoxy-d-glucose BEC blood EC Humans Glycolysis PPAR alpha Receptor Fibroblast Growth Factor Type 1 HK2 hexokinase 2 ERK extracellular signal–regulated protein kinase LEC lymphatic endothelial cell Molecular Biology fatty acid oxidation CPT1A carnitine palmitoyltransferase 1A Cell Proliferation chemistry.chemical_classification biology Carnitine O-Palmitoyltransferase Chemistry lymphatic endothelial cell EC endothelial cell HDLEC human dermal LEC Endothelial Cells Cell Biology glycolysis Cell biology FGF fibroblast growth factor Endothelial stem cell Metabolic pathway ERK AMPK AMP-activated protein kinase Gene Knockdown Techniques fibroblast growth factor receptor biology.protein qPCR quantitative PCR Research Article Signal Transduction |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Metabolic flexibility is the capacity of cells to alter fuel metabolism in response to changes in metabolic demand or nutrient availability. It is critical for maintaining cellular bioenergetics and is involved in the pathogenesis of cardiovascular disease and metabolic disorders. However, the regulation and function of metabolic flexibility in lymphatic endothelial cells (LECs) remain unclear. We have previously shown that glycolysis is the predominant metabolic pathway to generate ATP in LECs and that fibroblast growth factor receptor (FGFR) signaling controls lymphatic vessel formation by promoting glycolysis. Here, we found that chemical inhibition of FGFR activity or knockdown of FGFR1 induces substantial upregulation of fatty acid β-oxidation (FAO) while reducing glycolysis and cellular ATP generation in LECs. Interestingly, such compensatory elevation was not observed in glucose oxidation and glutamine oxidation. Mechanistic studies show that FGFR blockade promotes the expression of carnitine palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme of FAO; this is achieved by dampened extracellular signal–regulated protein kinase activation, which in turn upregulates the expression of the peroxisome proliferator–activated receptor alpha. Metabolic analysis further demonstrates that CPT1A depletion decreases total cellular ATP levels in FGFR1-deficient rather than wildtype LECs. This result suggests that FAO, which makes a negligible contribution to cellular energy under normal conditions, can partially compensate for energy deficiency caused by FGFR inhibition. Consequently, CPT1A silencing potentiates the effect of FGFR1 knockdown on impeding LEC proliferation and migration. Collectively, our study identified a key role of metabolic flexibility in modulating the effect of FGFR signaling on LEC growth. |
| Databáze: | OpenAIRE |
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